Acquired immune deficiency syndrome (AIDS) has been reported in the hemophiliac population. Recent studies have demonstrated a high frequency of immunoregulatory defects among hemophiliacs receiving large donor-pool commercial factor VIII concentrates. Based on results of a pilot study we have formulated the following hypothesis: that defects in immunoregulation observed in patients with hemophilia may be the result of chronic reactivation of EBV and CMV infection secondary to bombardment of the immune system with large doses of alloantigens which are contained in multidonor lyophilized factor VIII preparations. This hypothesis will be examined by the following three approaches: 1) The relationship of cellular immune function (CMI) to experience with EBV and CMV will be studied among 240 patients with classic hemophilia currently treated with commercial factor VIII concentrates prepared from large donor pools. 2) The natural history of the immunoregulatory defects, in particular their potential for reversal with decreased alloantigen exposure, will be determined by serial CMI studies on 60 initially abnormal patients who will be randomized to receive either single donor cryoprecipitate, limited donor pool concentrate, or to continue on large donor pool commercial concentrate. 3) The specific role of herpesvirus infection and the amount of alloantigen exposure in producing immunoregulatory defects will be determined by prospective study of 50 hemophiliacs initially seronegative to both EBV and CMV having normal CMI, who will be randomized to receive either limited donor pool or large donor pool factor VIII concentrate and followed for 4 years. When the proposed studies are completed, we will be able to construct a dose-response curve for alloantigen exposure and development or reversal of defective CMI, as well as to make temporal correlations between acquisition of EBV and CMV and the development of persistent immunoregulatory dysfunction. These studies will provide useful information concerning the development and maintenance of abnormal immunoregulation in man. They will also contribute important information as to the clinical significance of the immune deficits and the effect on the immune system of alternative forms of factor replacement in classic hemophilia.